OP0012 INTERFERON-α MEDIATED THERAPEUTIC RESISTANCE IN EARLY RA IMPLICATES EPIGENETIC REPROGRAMMING
Authors: F. Cooles, J. Tarn, D. Lendrem, N. Naamane, A. Lin, B. Millar, N. Maney, N. Thalayasingam, V. Bondet, D. Duffy, M. Barnes, G. Smith, S. Ng, D. Watson, R. Henkin, A. Cope, L. Reynard, A. Pratt, R. M. Consortium, J. Isaacs
Journal: Annals of the Rheumatic Diseases (2022)

Background An interferon gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients. We previously demonstrated it negatively impacts on initial disease outcomes. Objectives To 1) reproduce previous findings demonstrating the harmful effects of the IGS on early RA clinical outcomes, 2) identify which IFN class is responsible for the IGS and 3) seek evidence that IFN-α exposure contributes to harmful epigenetic footprint at disease onset. Methods In a large multicentre inception cohort (n=190) of eRA patients (RA-MAP TACERA) whole blood transcriptome, IGS ( MxA, IFI44L, OAS1, ISG15, IFI6 ) and circulating interferons (IFN)-α, -β, -γ and -λ was examined at baseline and 6 months in conjunction with disease activity and clinical characteristics. A separate eRA cohort of paired methylome and transcriptome from CD4 T and CD19 B cells (n=41 for each) was used to explore any epigenetic influence of the IGS. Results The baseline IGS reproducibly and significantly negatively impacts on 6-month clinical outcomes. In the high IGS cohort there was increased DAS-28 (p=0.025) and reduced probability of achieving a good EULAR response (p=0.034) at 6-months. In addition, the IGS in eRA is shown for the first time to predominantly reflect raised circulating IFN-α protein, not other classes of IFN and examination of whole blood upstream nucleic acid sensors expression suggest a RNA trigger. Both the IGS and IFN-α significantly fell in parallel at 6 months (p&lt;0.0001), whereas other classes of IFN remained statistically static. There was a significant association with IFN-α and RF titre but not ACPA. Comparison of CD4 T and CD19 B cells between IGS high and low eRA patients demonstrated differentially methylated CPG sites and altered transcript expression of disease relevant genes e.g. PARP9, STAT1, EPTSI1 which was similarly, and persistently, altered 6 months in the separate TACERA cohort. Differentially methylated CPGs implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α) which cumulatively suggested IFN-α induced epigenetic changes promoting increased, and sustained, lymphocyte activation, proliferation and loss of anergy in the IGS high cohort. Conclusion We validate that the IGS is a robust prognostic biomarker in eRA predicting poor therapeutic response. Its persistent harmful effects may be driven via epigenetic modifications. These data have relevance for other IFN-α states, such as COVID-19, but also provide a rationale for the initial therapeutic targeting of IFN-α signalling, such as with JAKi, at disease onset in stratified eRA subsets. References nil Acknowledgements JDI is a National Institute for Health Research (NIHR) Senior Investigator. The authors acknowledge the support of TACERA Principal Investigators from all contributing NHS sites and the members of the TACERA Study Steering and Data Monitoring Committee. Additional acknowledgements include patient volunteers and administrative support from Ben Hargreaves. Newcastle researchers received infrastructural support via the Versus Arthritis Research into Inflammatory Arthritis Centre (Ref 22072), funding from The Medical Research Council; Academy of Medical Sciences; British Society of Rheumatology; The Wellcome Trust; JGW Patterson Foundation; Immune-Mediated Inflammatory Disease Biobank in the UK (IMID-Bio-UK), ANR and RTCure. This work was supported by the NIHR Newcastle Biomedical Research Centre at Newcastle Hospitals Foundation Trust and Newcastle University; views expressed are the authors’ and not necessarily those of the National Health Service, the National Institute of Health Research or the Department of Health. Disclosure of Interests Faye Cooles Speakers bureau: Astrazeneca: December 2021, Jessica Tarn: None declared, Dennis Lendrem: None declared, Najib Naamane: None declared, Alice Lin: None declared, Ben Millar: None declared, Nicola Maney: None declared, Nishanthi Thalayasingam: None declared, Vincent Bondet: None declared, Darragh Duffy: None declared, Michael Barnes: None declared, Graham Smith: None declared, Sandra Ng: None declared, David Watson: None declared, Rafael Henkin: None declared, Andrew Cope: None declared, Louise Reynard: None declared, Arthur Pratt: None declared, RA-MAP Consortium: None declared, John Isaacs Speakers bureau: speaker/consulting fees from AbbVie, Gilead, Roche and UCB., Grant/research support from: JDI discloses research grants from Pfizer, Janssen and GSK.